There is mounting evidence that diabetes mellitus affects retinal neurons before abnormalities of the retinal vasculature are apparent clinically. However, relatively little is known about these neural deficits and how they affect visual function in diabetic patients who have minimal or no clinically-apparent diabetic retinopathy (M/N DR). The objective of this proposal is to develop and apply novel approaches for characterizing the nature and extent of visual dysfunction and its potential relationship to neural processes in M/N DR patients. Achieving this objective will provide important new insight into neural dysfunction in patients who have M/N DR and will establish new tests that are capable of classifying patients who have not yet developed clinically- apparent retinopathy, a group that cannot be staged or subtyped according to standard scales. This new insight and the ability to subtype these patients would be of great use in clinical trials that aim to slow or prevent neurodegeneration. Three complementary aims are proposed that use imaging, psychophysical, and electrophysiological techniques to provide new views of retinal function and structure in M/N DR patients and to address important questions generated by our preliminary investigations: Aim 1 will determine the relationship between contrast sensitivity deficits and retinal structure in M/N DR patients by simultaneously acquiring microperimetric contrast sensitivity measurements and optical coherence tomography measurements. Aim 2 will identify the mechanisms underlying electrophysiological abnormalities in these patients by measuring the electroretinogram (ERG) using standard full-field brief flashes of light, contrast- modulated sinewave flicker, focal maculr ERGs, and multi-focal ERGs. This comprehensive battery of electrophysiological tests will be used to challenge common assumptions regarding the sites of disease action that underlie ERG abnormalities. Aim 3 will measure and model contrast sensitivity deficits in diabetic patients who have M/N DR using a visual-luminance-noise-based paradigm that will provide insight into sites and mechanisms of disease action. After accomplishing these aims, we will have: 1) established clinically-applicable approaches to vision assessment that can quantify neural abnormalities in diabetic patients who have M/N DR; 2) gained new insight into the sites and mechanisms that underlie impairments in visual function in these patients. This line of study is particularly important and timely as new therapeutic approaches for treating early- stage retinopathy are being investigated, but the tools that are currently available to subtype patients and evaluate therapeutic efficacy lag behind.